The present invention is directed to absorbable polyesters comprising one or more monophosphate functionality; a conjugate comprising the foregoing polyester and a peptide and/or a bioactive agent; microparticles comprising an absorbable polyester; a conjugate comprising the microparticles and a peptide and/or a bioactive agent; an acylated or alkylated polysaccharide having one or more monophosphate functionality; a conjugate comprising the acylated or alkylated polysaccharide and a peptide and/or a bioactive agent; and pharmaceutical compositions thereof.
Phosphorous-containing heterochain polymers have been cited in the patent and technical literature in conjunction with (1) flame-retardant and/or hydrophilic polyamides (Shalaby, S. W., et al., J. Polym. Sci., Polym. Chem. Ed., 12, 2917 (1974); Shalaby, S. W., et al., J. Polym. Sci., Polym. Chem. Ed., 13, 669 (1975); Shalaby, S. W., et al., J. Polym. Sci., Polym. Chem. Ed., 14, 2675 (1976); Shalaby, S. W. and McCaig, S., U.S. Pat. No. 5,491,198; Shalaby, S. W. and Rogers, K. R., U.S. Pat. No. 5,558,517); (2) flame-retardant polyesters (Heffner, R. E., U.S. Pat. No. 4,420,587; Koch, P. J., et al., J. Appl. Polym. Sci., 19, 227 (1975); Japanese Pat. 51-40432); (3) flame-retardant polyurethanes and epoxy resins (German Patent DE 1,292,862, U.S. Pat. No. 3,321,555); (4) thermally stable polyesters with chain end-groups reacted with phosphonyl thiocyanate (U.S. Pat. No. 3,838,045); (5) phosphorylated cellulose as a cation-exchanger (DD 286600); and (6) phosphorylated polyesters as semiconducting materials (SU, 672878). However, there is no disclosure in the art of incorporation of phosphate groups at available hydroxy end-group sites of absorbable polyesters, which sites are typically present at one or two terminals of the chain. This is not surprising since conditions of chemical reactions known for hydroxy group phosphorylation could cause hydrolysis of the highly reactive absorbable polyester chains. Meanwhile, there has been great interest in developing carboxyl-bearing absorbable polyesters for use in forming conjugates with bioactive polypeptides as controlled release systems therefor (Shalaby, S. W., et al., U.S. Pat. No. 5,672,659).
Therefore, there is an incentive to make directly phosphorylated absorbable polyesters without significantly causing chain degradation to obtain novel controlled release systems.